U.S. patent number 9,161,943 [Application Number 11/967,315] was granted by the patent office on 2015-10-20 for sustained release composition and manufacturing method thereof.
This patent grant is currently assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE. The grantee listed for this patent is Sung En Chen, Po Hong Lai, Chiao Pin Li, John Jianghann Lin, Min-Ying Lin, Chia-Wen Liu, Yo Wen Lo, Jui-Mei Lu, Ming-Thau Sheu. Invention is credited to Sung En Chen, Po Hong Lai, Chiao Pin Li, John Jianghann Lin, Min-Ying Lin, Chia-Wen Liu, Yo Wen Lo, Jui-Mei Lu, Ming-Thau Sheu.
United States Patent |
9,161,943 |
Lu , et al. |
October 20, 2015 |
Sustained release composition and manufacturing method thereof
Abstract
A sustained release composition comprising a polymer and
manufacturing method thereof. The sustained release composition
comprises a polymer, a bioactive agent, and a release rate
determined agent, wherein the release rate determined agent is
dispersed in the sustained release composition to control the
release rate of the bioactive agent. The method comprises providing
an oil phase comprising a bioactive agent, a polymer, and a release
rate determined agent; providing an aqueous phase comprising a
surfactant; mixing the oil phase with the aqueous phase to form the
sustained release composition having a controlled release
effect.
Inventors: |
Lu; Jui-Mei (Jhudong Township,
Hsinchu County, TW), Liu; Chia-Wen (Yangmei Township,
Taoyuan County, TW), Lai; Po Hong (Pingjhen,
TW), Lin; John Jianghann (Keelung, TW), Li;
Chiao Pin (Kaohsiung, TW), Chen; Sung En
(Kaohsiung Country, TW), Lo; Yo Wen (Shueishang
Township, Chiayi County, TW), Sheu; Ming-Thau
(Sijhih, TW), Lin; Min-Ying (Hsinchu, TW) |
Applicant: |
Name |
City |
State |
Country |
Type |
Lu; Jui-Mei
Liu; Chia-Wen
Lai; Po Hong
Lin; John Jianghann
Li; Chiao Pin
Chen; Sung En
Lo; Yo Wen
Sheu; Ming-Thau
Lin; Min-Ying |
Jhudong Township, Hsinchu County
Yangmei Township, Taoyuan County
Pingjhen
Keelung
Kaohsiung
Kaohsiung Country
Shueishang Township, Chiayi County
Sijhih
Hsinchu |
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
TW
TW
TW
TW
TW
TW
TW
TW
TW |
|
|
Assignee: |
INDUSTRIAL TECHNOLOGY RESEARCH
INSTITUTE (Hsinchu, TW)
|
Family
ID: |
40798742 |
Appl.
No.: |
11/967,315 |
Filed: |
December 31, 2007 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20090169632 A1 |
Jul 2, 2009 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/5031 (20130101); A61P 43/00 (20180101); A61K
31/70 (20130101); A61K 9/1647 (20130101); A61K
31/7088 (20130101); A61K 9/0019 (20130101) |
Current International
Class: |
A61K
31/70 (20060101); A61K 9/16 (20060101); A61K
9/50 (20060101); A61K 9/00 (20060101); A61K
31/7088 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
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2001517685 |
|
Oct 2001 |
|
JP |
|
2007500229 |
|
Jan 2007 |
|
JP |
|
2007524645 |
|
Aug 2007 |
|
JP |
|
2009155302 |
|
Jul 2009 |
|
JP |
|
2009543849 |
|
Dec 2009 |
|
JP |
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9628143 |
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Sep 1996 |
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WO |
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9709985 |
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Mar 1997 |
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WO |
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2004089291 |
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Oct 2004 |
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WO |
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2005049090 |
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Jun 2005 |
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WO |
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Aug 2005 |
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WO |
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WO 2005070332 |
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Aug 2005 |
|
WO |
|
2006036614 |
|
Apr 2006 |
|
WO |
|
2008026894 |
|
Mar 2008 |
|
WO |
|
Other References
Mu et al, Vitamin E TPGS Used As an Emulsifier in the Solvent
Evaporation/Extraction Technique for Fabrication of POlymeric
Nanospheres for Controlled Release of Paclitaxel (Journal of
Controlled Release 80 (2002) 129-144). cited by examiner .
Single et al, Paclitaxel and Its Formulations, International
Journal of Pharmaceutics 235 (2002), 179-192. cited by examiner
.
Mu, L.; Feng, S.S. "Vitamin E TPGS used as emulsifier in the
solvent evaporation /extraction technique for fabrication of
polymeric nanospheres for controlled release of paclitaxel (Taxol)"
Journal of Controlled Release 80 (2002) 129-144. cited by examiner
.
Diaz, R.V.; Soriano, I.; Delgado, A.; Llabres, M.; Evora, C.
"Effect of surfactant agents on the release of 125I-bovine
calcitonin from Plga microspheres: in vitro-in vivo study." Journal
of Controlled Release 43 (1997) 59-64. cited by examiner .
Singla, A.K.; Garg, A.; Aggarwal, D. "Paclitaxel and its
formulations" International Journal of Pharmaceutics 235 (2002)
179-192. cited by examiner .
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(http://www.innovate-excipients.basf.com/Products.aspx?PRD=30035120),
accessed Jul. 18, 2013. cited by examiner .
Rongyi, L. "In Vitro Study of Anticancer Drug Doxorubicin in
PLGA/PLA Based Microparticles" 2005, pp. 1-93. cited by examiner
.
JP Office Action mailed Jan. 12, 2010. cited by applicant .
English abstract of JP2007524645, pub. Aug. 30, 2007. cited by
applicant .
English abstract of JP2009543849, pub. Dec. 10, 2009. cited by
applicant .
"Effect of Surfactant Agents on the Release of 125I-bovine
Calcitonin from PLGA microspheres: in vitro--in vivo study" R.V.
Diaz et al., Journal of Controlled Release, Mar. 1996. cited by
applicant .
"Optimization of Formulation Variables for the Development of Long
Acting Microspheres Based Depot Injection of Olanzapine" T. Nahata
et al., Journal of Microencapsulation, Sep. 2008. cited by
applicant .
Chinese language office action dated Apr. 14, 2011. cited by
applicant .
Japanese language office action dated Oct. 23 2012. cited by
applicant .
English language translation of office action. cited by applicant
.
English language translation of abstract of JP 2001517685
(published Oct. 9, 2001). cited by applicant .
English language translation of abstract of JP 2007500229
(published Jan. 11, 2007). cited by applicant .
English language translation of abstract of JP 2009155302
(published Jul. 16, 2009). cited by applicant .
Taiwanese language office action dated Nov. 25, 2011. cited by
applicant .
Zhang, Z., et al.; "The Drug Encapsulation Efficiency, In Vitro
Drug Release, Cellular Uptake and Cytotoxicity of Paclitaxel-Loaded
Poly(lactide)-Tocopheryl Polyethylene Glycol Succinate
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applicant .
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applicant.
|
Primary Examiner: Kwon; Brian-Yong
Assistant Examiner: Rosenthal; Andrew S
Attorney, Agent or Firm: McClure, Qualey & Rodack,
LLP
Claims
What is claimed is:
1. A sustained release composition without lag phase comprising a
polymer, a bioactive agent, and a release rate determined agent,
wherein the bioactive agent and the release rate determined agent
are dispersed in the sustained release composition, the release
rate determined agent is vitamin E-TPGS present in amounts of
7%-42% by weight of the total weight of the sustained release
composition for controlling the release rate of the bioactive
agent, wherein the polymer is polylactide-co-glycolide (PLGA) and
the bioactive agent is olanzapine, and wherein the sustained
release composition is produced by an emulsion process comprising
an oil phase including the bioactive agents, the polymer and the
release rate determined agent before mixing with an aqueous
phase.
2. The sustained release composition as claimed in claim 1, wherein
the sustained release composition continually releases the
bioactive agent.
3. The sustained release composition as claimed in claim 1, wherein
the sustained release composition has an encapsulation rate of
bioactive agent exceeding 70%.
4. The sustained release composition as claimed in claim 1, wherein
the sustained release composition is a microsphere, microparticle,
or microcapsule.
5. The sustained release composition as claimed in claim 4, wherein
the microsphere, microparticle, or microcapsule has a diameter
exceeding 5 .mu.m.
6. The sustained release composition as claimed in claim 1, wherein
the sustained release composition is used for intramuscular or
subcutaneous injection.
7. A method for manufacturing a sustained release composition as
claimed in claim 1, comprising: (a) providing an oil phase
comprising olanzapine, polylactide-co-glycolide (PLGA), and vitamin
E-TPGS; (b) providing an aqueous phase comprising a surfactant; (c)
mixing the oil phase with the aqueous phase to form the sustained
release composition; and (d) recovering the composition.
8. The method as claimed in claim 7, wherein the oil phase further
comprises a solvent.
9. The method as claimed in claim 8, wherein the solvent comprises
methylene chloride, ethyl acetate, benzyl alcohol, acetone, acetic
acid, propylene carbonate, dichloromethane, chloroform,
1,4-dioxane, dimethylformamide (DMF), dimethyl sulphoxide (DMSO),
toluene, or tetrahydrofuran (THF).
10. The method as claimed in claim 7, wherein the surfactant
comprises polyvinyl alcohol (PVA), NP-5, Triton x-100, Tween 80,
PEG 200-800, sodium dodecyl sulfate (SDS), alcohol ethoxylates,
alkylphenol ethoxylates, secondary alcohol ethoxylates, fatty acid
ester, or alkyl polyglycosides.
11. The method as claimed in claim 7, wherein the release rate
determined agents has a final concentration of about 7 to 42% by
weight.
12. The method as claimed in claim 7, wherein the sustained release
composition is a microsphere, microparticle, or microcapsule.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a sustained release system, and in
particular relates to a sustained release composition containing
release rate determined agent.
2. Description of the Related Art
The desirability of coating medical devices such as, surgical
implants, sutures and wound dressings with pharmaceutical agents is
well known. Such coated devices provide a means for locally
delivering pharmaceutical or therapeutic agents at the site of
medical intervention to treat a variety of diseases. For example,
surgical implants or sutures coated with antibiotics can provide
local delivery of antibiotics directly to an implantation or suture
site, thereby decreasing the onset of infection following the
surgical intervention.
Thus, there is an increasing interest in developing a drug delivery
system which is both safe and which provides a high biological
availability of the drug, i.e. to maximize pharmaceutical activity
of known drugs as well as to minimize the side effects thereof. Due
to their uniform release rate during a given time period and the
non-toxic property of degradation products, biodegradable polymers
have been widely investigated as drug carriers. Biodegradable
polymer drug carriers are especially useful for delivering drugs
requiring continuous and sustained release with a single
administration, e.g. peptide or protein drugs, which should be
administered daily because of quick loss of activity in the
body.
However, the traditional drug release curve includes three phases
with an initial release phase, a lag phase, and a secondary release
phase, wherein the drugs are only released at initial and secondary
release phases. Thus, at the lag phase, it is necessary to combine
an oral administration with the local administration to achieve a
desired therapeutic goal, with the additional oral administration
increasing costs and causing inconvenience. To overcome the above
problems, a novel sustained release composition and manufacturing
method thereof are needed.
BRIEF SUMMARY OF INVENTION
The invention provides a sustained release composition, comprising
a polymer, a bioactive agent, and a release rate determined agent,
wherein the bioactive and the release rate determined agent are
dispersed in the sustained release composition, and the release
rate determined agent controls a release rate of the bioactive
agent.
The invention further provides a method for manufacturing a
sustained release composition, comprising: providing an oil phase
comprising a bioactive agent, a polymer, and release rate
determined agent; providing an aqueous phase comprising a
surfactant; mixing the oil phase with the aqueous phase to form the
sustained release composition having a controlled release
effect.
The invention further provides a method for treating an animal,
comprising administering a pharmaceutically effective amount of the
sustained release composition of the invention.
A detailed description is given in the following embodiments with
reference to the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
The present invention can be more fully understood by reading the
subsequent detailed description and examples with references made
to the accompanying drawings, wherein:
FIG. 1 shows the drug release curve of the sustained release
compositions.
DETAILED DESCRIPTION OF INVENTION
The following description is of the best-contemplated mode of
carrying out the invention. This description is made for the
purpose of illustrating the general principles of the invention and
should not be taken in a limiting sense. The scope of the invention
is best determined by reference to the appended claims.
The invention provides a sustained release composition, comprising
a polymer, a bioactive agent, and a release rate determined agent,
wherein the bioactive and the release rate determined agent are
dispersed in the sustained release composition, and the release
rate determined agent controls a release rate of the bioactive
agent.
The sustained release composition may contain one or more of the
bioactive agents, which include nucleic acids, carbohydrates,
peptides, proteins, small molecule pharmaceutical substances,
immunogens, antineoplastic agents, or hormones. Examples of nucleic
acids include, but are not limited to, DNAs, RNAs, chemically
modified DNAs and chemically modified RNAs, aptamers, antisense
oligonucleotides, RNA interferences, and small interfering RNAs.
Examples of carbohydrates include, but are not limited to, heparin,
low molecular weight heparin and the like. Examples of peptides
include, but are not limited to, LHRH agonists and synthetic
analogs, leuprolide, somatostatin analogs, hormones, octreotides,
glucagons-like peptides, oxytocins and the like. Examples of
proteins include, but are not limited to, antibodies, therapeutic
proteins, human growth hormones (such as bone morphogenetic
protein, TGF-.beta.1, fibroblast growth factor, platelet-derived
growth factor, or insulin-like growth factor), oxytocins,
octreotides, gonadotropin-releasing hormones, leuprolide,
interferons, insulin, calcitonin, interleukin, and the like.
Examples of small molecule pharmaceutical substances include, but
are not limited to, antiinfective agents (e.g. amphotericin B),
cytotoxic agents, antihypertensive agents, antifungal agents (e.g.
fluconazole, itraconazole, ketoconazole), antipsychotic agents
(e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole,
ziprasidone, or quetiapine), antidiabetic agents, immune stimulants
(e.g. .beta.-1,3/1,6-glucans), immune suppressants (e.g.
cyclosporine, or prednisone), antibiotics (e.g. penicillin,
cephalosprins, vancomycin hydrochloride, or lincomycin),
antivirals, anticonvulsants, antihistamines, cardiovascular agents,
anticoagulants, hormones, antimalarial, analgesics, anesthetics,
steroids, nonsteroidal anti-inflammatories, and antiemetics.
Examples of hormones include, but are not limited to, growth
factor, melatonin, serotonin, thyroxin, triiodothyronine,
epinephrine, norepinephrine, dopamine, adiponectin,
angiotensinogen, cholecystokinin, erythropoietin, gastrin,
glucagon, inhibin, secretin, thrombopoietin, or aldosterone. The
bioactive agent can be present in the oil phase at a concentration
of 0.1-10% by weight, preferably, 2% by weight.
The polymers dissolved in the solvent is a bio-molecule
(biodegradable polymer), for example, phospholipids, lecithin,
poly(lactiide)s, poly(glycolide)s, polylactide-co-glycolide (PLGA),
polyglutamic acid, polycaprolactone (PCL), polyanhydrides,
polyamino acid, polydioxanone, polyhydroxybutyrate,
polyphophazenes, polyesterurethane,
polycarbosyphenoxypropane-cosebacic acid, polycarbonates,
polyesteramides, polyacetyls, polycyanoacrylates, polyetheresters,
poly(alkylene alkylate)s, or copolymers thereof. The hydrophobic
polymer can be degraded in the biological subject without
impact.
TPGS (d-alpha-tocopheryl polyethylene glycol succinate) is
commercially available from Eastman Chemical Company as "Vitamin
E-TPGS". Vitamin E-TPGS is a water soluble derivative of natural
source vitamin E, and similar to an amphiphile. In the invention,
various chemical derivatives of vitamin E-TPGS including ester and
ether linkages of various chemical moieties are included within the
definition of vitamin E-TPGS. Rather, it is dispersed in the oil
phase to control the release of the bioactive agent. According to
an important feature of the invention, the drug release curve of
the sustained release composition of the invention does not have a
lag phase. Thus, the bioactive agent can be continuously released,
which obviates the need for using additional oral administration.
In the invention, TPGS is present in as amount of about 1 to 50% by
weight of the total weight of the sustained release composition,
preferably, 4 to 15% by weight.
In one embodiment, the sustained release composition is in form of
a microparticle, microsphere, or microcapsule. Microsphere is
typically approximately homogeneous in composition and
microcapsules comprise a core of a composition distinct from a
surrounding shell. For purposes of this disclosure, the terms
microsphere, microparticle and microcapsule are used
interchangeably. In another embodiment, the sustained release
composition of the invention has a drug encapsulation rate
exceeding 70%, preferably, 70% to 99.9%, a diameter exceeding 5
.mu.m, preferably, 5 .mu.m to 200 .mu.m, most preferably 30 .mu.m
to 100 .mu.m, and can continuously release the bioactive agent in
the biological body in absence of the lag phase.
The sustained release compositions of the present invention can be
applied systemically or topically. For example, the compositions
can be administered by injection intramuscularly, intraperitoneally
intravenously or subcutaneous. Additionally, the compositions can
be in virtually any form, for example, lotions, ointments, creams,
gels, drops, suppositories, sprays, liquids and powders.
Conventional pharmaceutical carriers, aqueous, powder or oily
bases, thickeners and the like may be incorporated.
The invention further provides a method for manufacturing a
sustained release composition. The method comprises providing an
oil phase; providing an aqueous phase comprising a surfactant; and
mixing the oil phase with the aqueous phase to form a sustained
release composition, wherein the oil phase contains a bioactive
agent, a polymer, and a release rate determined agent.
As used herein, the term "oil phase" of the invention refers to the
solution of the solvent, polymer, bioactive agent, and release rate
determined agent, that will be mixed with an aqueous phase through
emulsion process to provide the sustained release composition of
the invention. The solvent of the oil phase includes, but are not
limited to, methylene chloride, ethyl acetate, benzyl alcohol,
acetone, acetic acid, propylene carbonate, dichloromethane,
chloroform, 1,4-dioxane, dimethylformamide (DMF), dimethyl
sulphoxide (DMSO), toluene, or tetrahydrofuran (THF).
The terms "release rate determined agent" of the invention refers
to the solution of the surfactants which can control the release
rate of the bioactive agent.
The release rate determined agent of the invention include, but are
not limited to, Span.RTM. 80, Span.RTM. 85, oleic acid, PEG-PCL
di-block copolymer, glyceryl tricaprylate, Pluronic.RTM. (F68),
Tween.RTM. 80 or vitamin E-TPGS.
The terms "aqueous phase" refers to the solution of water and
surfactants that is contacted with an oil phase through an emulsion
process to provide the sustained release compositions of the
present invention. The release rate determined agent are present at
a concentration in the oil phase between 1 and 50% by weight. For
example, they are present at a concentration between 4 to 15% by
weight.
The surfactants of the invention include, but are not limited to,
polyvinyl alcohol (PVA), NP-5, Triton X-100, Tween.RTM. 80, PEG
200-800, sodium dodecyl sulfate (SDS), alcohol ethoxylates,
alkylphenol ethoxylates, secondary alcohol ethoxylates, fatty acid
ester, or alkyl polyglycosides. The surfactants are present at a
concentration in the aqueous between 0.1 and 10% by weight. For
example, they are present at a concentration between 0.1 to 5% by
weight.
In one embodiment, the oil phase is contacted with the aqueous
phase to form an emulsion, wherein the emulsion comprises droplets
of the oil phase dispersed in the aqueous phase. Solvent is
subsequently removed from the emulsion droplets to form hardened
microparticles. The solvent can be removed by evaporation,
filtration, or extraction into an extraction liquid. For example,
the extraction liquid may be water. The hardened microparticles may
then be recovered from the aqueous phase and dried.
The emulsion is produced by stirring the organic and aqueous
phases. In one embodiment, the emulsion is produced by use of a
mixer, such as a static mixer. Alternatively, the emulsion is
produced by use of turbulent mixing.
The emulsion process may be carried out at any temperature between
the boiling point and freezing point of the components. In one
embodiment, the temperature ranges from 0.degree. C. to 100.degree.
C., or between about 5.degree. C. to 75.degree. C., or between
about 15.degree. C. and about 60.degree. C.
Additionally, cosolvents may be added to the oil phase. They are
optionally used to promote solubility of the bioactive agent in the
oil phase. In one embodiment, they include, but are not limited to,
dimethyl sulfoxide, dimethyl formamide, n-methylpyrrolidinone, PEG
200, PEG 400, methyl alcohol, ethyl alcohol, isopropyl alcohol, and
benzyl alcohol. The cosolvent may be present between 0 and 90% by
weight of the solvent of the oil phase, or between 0 and 50% by
weight of the solvent of the oil phase. The bioactive agent may be
dissolved first in an appropriate volume of the cosolvent which is
then added to the solvent of the oil phase, optionally dissolved
with the biodegradable polymer, so as to form a solution containing
all the components of the oil phase. It should be noted that, a
person of ordinary skill may adjust the volumes and order of
addition to achieve the desired solution of bioactive agent and
biodegradable polymer. In one embodiment, the bioactive agent will
be present in the oil phase at a concentration of 0.1 to 10% by
weight. In another embodiment, the biodegradable polymer will be
present in the oil phase at a concentration of 0.1 to 20% by
weight. For example, the biodegradable polymer will be present in
the oil phase at a concentration of 1 to 10% by weight.
The invention further provides a method for treating an animal,
comprising administering a pharmaceutically effective amount of the
sustained release composition of the invention. The animal is not
necessary to combine an oral administration with the local
administration to improve treatment effects, because the sustained
release composition can continuously release bioactive agent.
The sustained release compositions of the invention may be
suspended in any aqueous solution or other diluent for injection in
a human or animal patient in need of treatment. Aqueous diluent
solutions may further include a viscosity enhancer selected from
the group consisting of sodium carboxymethylcellulose, sucrose,
mannitol, dextrose, trehalose and other biocompatible viscosity
enhancing agents.
The "animal" of the invention refers as used herein refers to any
animal of the class Mammalia. A mammalian animal of the invention
includes, human or non-human mammal, e.g. a dog, a cat, a mouse, a
rat, a cow, a sheep, a pig, a goat, or a primate, and expressly
includes laboratory mammals, livestock, and domestic mammals. In
one embodiment, the mammals may be a human; in others, the mammal
may be a rodent, such as a mouse or a rat.
EXAMPLE
Example 1
50/50 PLGA Microspheres Contained 0, 7, 26, 42% Vitamin-E TPGS
80 mg of olanzapine, 200 mg PLGA (LA/GA ratio=50/50, M.W.=43000)
and distinct amount vitamin E-TPGS (0, 7, 26, 42% by weight) were
co-dissolved in 5 mL of dichloromethane to form an oil phase. The
oil phase was dropped into 1000 mL of cooled aqueous phase
containing 0.1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm.
The resulting o/w emulsion was agitated continuously for 3 h at
room temperature. The microspheres were collected by
centrifugation, washed with F68, water and freeze-dried. Then the
microspheres were evaluated for particle size and drug encapsulated
efficiency by Multisizer and High Performance Liquid Chromatography
(HPLC). The results showed that the particle size were
68.4.+-.28.3, 71.6.+-.27.3, 91.0.+-.35.8, 101.9.+-.42.8 .mu.m and
the encapsulated efficiency were 77.7, 83.5, 85.9, 85.2% of the
microspheres contained 0, 7, 26, 42% (w/w) vitamin E-TPGS,
respectively.
Example 2
85/15 PLGA Microspheres Contained 0, 4, 15, 26% Vitamin E-TPGS
320 mg of olanzapine, 800 mg PLGA (LA/GA ratio=85/15, M.W.=53000)
and distinct amount vitamin E-TPGS (0, 4, 15, 26% by weight) were
co-dissolved in 15 mL of dichloromethane to form an oil phase. The
oil phase was dropped into 2000 mL of cooled aqueous phase
containing 0.1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm.
The methods of agitation, collection and analysis are as previously
defined in Example 1. The results showed that the particle size
were 40.0.+-.21.3, 58.8.+-.28.4, 47.4.+-.21.4, 62.9.+-.25.9 .mu.m
and the encapsulated efficiency were 77.2, 74.7, 87.6, 83.7% of the
microspheres contained 0, 4, 15, 26% (w/w) vitamin E-TPGS,
respectively.
Example 3
50/50 PLGA Microspheres Contained a Different Aqueous Phase
80 mg of olanzapine, 200 mg PLGA (LA/GA ratio=50/50, M.W.=43000)
and 42% (w/w) of vitamin E-TPGS were co-dissolved in 5 mL of
dichloromethane to form an oil phase. The oil phase was dropped
into 1000 mL of a cooled aqueous phase and then emulsified at 1000
rpm, wherein the cooled aqueous phase included 0.05% PVA or 0.05%
PVA containing 0.5% gelatin. The resulting o/w emulsion was
agitated continuously for 3 h at room temperature. The microspheres
were collected by centrifugation, washed with F68, water and
free-dried. The analysis methods of the particle size and drug
encapsulated efficiency are as previously defined above. The
results showed that the particle size were 108.7.+-.37.3,
85.5.+-.31.4 .mu.m and the encapsulated efficiency were 74.1, 73.1%
of the microspheres contained 0.05% PVA without and with 0.5%
gelatine, respectively.
Example 4
85/15 PLGA Microspheres Contained a Different Oil Phase
320 mg of olanzapine, 800 mg PLGA (LA/GA ratio=85/15, M.W.=43000)
and 15 w/w % of vitamin E-TPGS were co-dissolved in 15 mL of
dichloromethane to form an oil phase. In this Example,
dichloromethane included pure dichloromethane (Formulation #1),
dichloromethane containing ethanol (DCM:ethanol=2:1, Formulation
#2), and dichloromethane containing acetone (DCM:acetone=2:1,
Formulation #3), respectively. The oil phase was dropped into 2000
mL of cooled aqueous phase containing 0.1% PVA and emulsified at
1000 rpm. The methods of agitation, collection and analysis are as
previously defined in Example 1. The results showed that the
particle size were 76.2.+-.31.4, 70.6.+-.31.8, 70.6.+-.31.8 .mu.m
and the encapsulated efficiency were 86.8, 89.7, 88.5% of the
microspheres in the Formulation #1, #2, #3.
Example 5
85/15 PLGA Microspheres Contained a Different LA/GA Ratio
320 mg of olanzapine, 800 mg of PLGA and 15% (w/w) vitamin E-TPGS
were co-dissolved in 15 mL of dichloromethane to form an oil phase,
wherein the PLGA had a different LA/GA ratio, which included
85/15:50/50=3:1 (Formulation #1), 85/15:50/50=1:3 (Formulation #2),
and 75/20:50/50=4:1 (Formulation #3), respectively. The oil phase
was dropped into 2000 mL of cooled aqueous phase containing 0.1%
PVA and emulsified at 1000 rpm. The methods of agitation,
collection and analysis are as previously defined in Example 1. The
results showed that the particle size were 62.2.+-.32.0,
59.1.+-.24.9, 41.1.+-.19.1 .mu.m and the encapsulated efficiency
were 84.9, 84.2, 83.2% of the microspheres in the Formulation #1,
#2, #3.
Example 6
75/25 PLGA Microspheres
320 mg of olanzapine, 800 mg PLGA (LA/GA ratio=75/25) and 4% (w/w)
of vitamin E-TPGS were co-dissolved in 15 mL of dichloromethane to
form an oil phase. In this Example, the molecule weight of the PLGA
was 30000 Da. and 21000 Da., respectively. The oil phase was
dropped into 2000 mL of cooled aqueous phase containing 0.1% PVA
and emulsified at 1000 rpm. The methods of agitation, collection
and analysis are as previously defined in Example 1. The results
showed that the particle size were 43.5.+-.18.8, 37.4.+-.20.2 .mu.m
and the encapsulated efficiency were 80.8, 77.6% of the
microspheres comprised of 30000, 21000 Da. PLGA, respectively.
Example 7
85/15 PLGA Microspheres
320 mg of olanzapine, 800 mg PLGA (LA/GA ratio=85/15) and 4% (w/w)
of vitamin E-TPGS were co-dissolved in 15 mL of dichloromethane to
form an oil phase. In this Example, the molecule weight of PLGA
included 53000 and 27000 Da., respectively. The methods of
agitation, collection and analysis are as previously defined in
Example 1. The results showed that the particle size were
58.8.+-.28.4, 43.9.+-.20.6 .mu.m and the encapsulated efficiency
were 74.7, 77.0% of the microspheres comprised of 53000, 27000 Da.
PLGA, respectively.
Example 8
Different Release Rate Determined Agents Formulations
320 mg of olanzapine, 800 mg PLGA (LA/GA ratio=85/15, M.W.=53000)
and distinct release rate determined agent (Span.RTM. 80, Span.RTM.
85, oleic acid, PEG-PCL di-block copolymer, glyceryl tricaprylate,
Pluronic.RTM., Tween.RTM. 80) were co-dissolved in 15 mL of
dichloromethane to form an oil phase. The oil phase was dropped
into 2000 mL of cooled aqueous phase containing 0.1% polyvinyl
alcohol (PVA) and emulsified at 1000 rpm. The methods of agitation,
collection and analysis are as previously defined in Example 1. The
results showed that the particle size were 46.7.+-.18.6,
40.3.+-.15.5, 46.3.+-.22.6, 55.7.+-.27.3, 49.5.+-.22.0,
68.1.+-.30.9, 30.1.+-.14.9 .mu.m and the encapsulated efficiency
were 86.9, 78.2, 79.4, 87.2, 69.5, 85.2, 75.5% of the microspheres
comprise distinct release rate determined agent, respectively.
Example 8
Drug Release In Vivo
Sprague-Dawley rats were selected for the evaluation of depot
formulations because the size of their leg muscles facilitates dose
administration and evaluation of the injection site.
The male Sprague-Dawley rats weight between 250 to 300 g. Rats were
given a single injection with a 20- or 21-gauge needle into the
biceps femoris. The dose volume varied with the concentration of
the formulation but did not exceed 1 mL per injection. The rats
were given 40 mg of olanzapine/kg body weight.
At each time point, a 0.1 mL blood sample was collected from the
lateral tail vein into heparanized collection tubes. Blood samples
were collected once prior to dose administration and at various
time points after dose administration throughout the 50-day period.
Typical time points are at 5 min, 10 min, 30 min, 1 hr, 2 hr, 4 hr,
6 hr, 1 d, 2 d, 4 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d,
35 d, 38 d, 42 d, 45 d, 50 d after dose administration. Plasma was
harvested and plasma concentration of olanzapine was determined by
HPLC/MS-MS.
Microsphere containing 15% (w/w) vitamin E-TPGS prepared in Example
2, was administrated into rats by intramuscular injection. In the
control groups, the TPGS of the microsphere was removed (PLGA only)
or substituted for Tween 80 (PLGA/Tween 80). Referring to FIG. 1,
microsphere containing TPGS continuously released olanzapine in the
rats, and the drug release curve of microsphere did not have the
lag phase.
While the invention has been described by way of example and in
terms of the preferred embodiments, it is to be understood that the
invention is not limited to the disclosed embodiments. To the
contrary, it is intended to cover various modifications and similar
arrangements (as would be apparent to those skilled in the art).
Therefore, the scope of the appended claims should be accorded the
broadest interpretation so as to encompass all such modifications
and similar arrangements.
* * * * *
References